1

Heparin InducedThrombocytopenia

Eric Kraut, MDProfessor of Internal Medicine

The Ohio State University Medical Center

• First recognized as complication of heparin in the 1970’s, but the understanding of pathogenesis, diagnosis, and treatment has occurred in the last ten years

• Heparin -induced thrombocytopenia is an antibody-mediated drug reaction that may be complicated not by just low platelets but arterial or venous thrombosis

Heparin Induced Thrombocytopenia

• Heparin –induced thrombocytopenia occurs in up to 5 % of patients receiving unfractionated heparin and in 0.5% receiving low–molecular weight heparin

• It can occur with miniscule amounts of heparin and the clinical situation effects frequency with orthopedic surgery and cardiac surgery more common than medical patients

Heparin Induced Thrombocytopenia

Temporal Aspects• In majority of patients the sentinel event

thrombocytopenia occurs four or more days after start of heparin

• However, rapid onset within 10 hours can occur in patients who received heparin within the last 100 days

2

Heparin-Induced Thrombocytopenia

Wartekin New England Journal of Medicine

Pathophysiology• HIT is a hypercoagulability state

associated with increased thrombin generation and increased risk of venous and arterial thrombosis

• This risk is maintained unabated for many days after heparin exposure

Pathophysiology• Heparin induces antibodies of IgG class

whose target is multimolecularcomplexes of platelet factor 4 and heparin bound to platelet surface

• These complexes occupy platelet FcγIIareceptors causing platelet activation and circulating platelet derived microparticles

3

Pathophysiology

Aster RH. New England Journal of Medicine 1995; 332:1374 [editorial].

When to Suspect• Thrombocytopenia with a drop of 50% or

greater from baseline is most common clinical finding

• Rare to have platelet counts less than 15x 109/L

• Thrombosis occurs in most patients with DVT more common than arterial

British Journal of Hematology

British Journal of Hematology

Factors Influencing theFrequency of HIT

4

Acute Systemic Reactions to Heparin Bolus

• Occurs 5-30 minutes after iv heparin bolus

• Prior heparin use with past 5-100 days• Abrupt fall but reversible drop in

platelet count

Acute Systemic Reactions to Heparin Bolus

• Chills, rigors, fever, flushing• Cardiorespiratory including arrest• Nausea , vomiting, diarrhea• Headache, rarely amnesia

Diagnosis• Clinical syndrome should be

confirmed by lab assay• May require assay off of heparin• Two major group of assays a) platelet

activation assays b)PF-4 dependent antigen assays

• Neither set of assays perfect

5

Management• HIT suspected but low probability follow

patient closely consider holding heparin follow platelet count and look for thrombosis ? Send assay

• HIT suspected intermediate or high probability stop heparin send assay anticoagulate

Management Decision

6

Heparin InducedThrombocytopenia

Spero Cataland, MDAssistant Professor of Internal MedicineThe Ohio State University Medical Center

Case Presentation #1• 67 year old male admitted for urgent CABG

doing well on post-operative day 3. Chest pain at surgical site and mild fatigue, but otherwise asymptomatic. Noted to have thrombocytopenia beginning 1 day after surgery

PMH: triple vessel CADFH: CAD, DMSH: non-smoker, rare alcohol use

Platelet Count

0

50

100

150

200

250

1 2 3 4 5 6 7 8 9 10 11

Days After Heparin

UFH at CABG

Thought Process• Relatively abrupt onset of

thrombocytopenia after cardiac bypass surgery

Exposure to heparin during heart lung bypassComplete blood count otherwise unremarkablePreviously normal platelet count prior to surgery

7

Warkentin, T. E. Chest 2005;127:35S-45S

Delayed-onset HIT

• Discontinue heparin administrationincluding unintended heparin exposures for catheter flushes, arterial line flushes, etc.avoid low molecular weight heparin as well given potential for cross-reactivity

• Is this enough?Incidence of new thrombotic events ranging 19%-52% in patients with discontinuation of heparin alone without additional anticoagulation

Heparin Induced Thrombocytopenia-Treatment

Heparin Induced Thrombocytopenia-Treatment

• Systemic anticoagulation with a direct thrombin inhibitor

argatroban and lepirudin approved for treatment by the United States FDA

Cannot wait for results of serologic testing

Heparin Induced Thrombocytopenia-Treatment

• Initiation of warfarin therapyDelay warfarin until substantial platelet recoveryAvoid unopposed warfarin therapyDuration of therapy 3-6 months

8

• Laboratory testing positive (functional assay) for the diagnosis of HIT

• Clinically asymptomatic, placed on systemic anticoagulation with Argatroban

Doppler study positive for lower extremity DVT

After normalization of platelet count started on warfarin therapy

• Received 4 months of warfarin therapy

Diagnosis

Case Presentation #2• 59 year old male, small bowel

obstruction, exploratory laparotomywith removal of infected mesh

PMH: chronic MRSA

FH: CVA, CHF

SH: non-smoker, no alcohol use

Case Presentation #2• Noted to have the development of

thrombocytopenia 5-6 days after SQ UFH

Started on IV heparin on day 4 after diagnosis of lower extremity DVTMore pronounced drop in platelet count after IV UFHWhich came first?• DVT versus HIT

9

Platelet Count

0

50

100

150

200

250

300

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17

Days

SQ UFH

DVT Diagnosed

IV UFH

HIT Testing

• Study by Oliveira et al of 2,420 patients treated with heparin for 4 days or longer

881 patients (36%) developed thrombocytopeniaMinority of patients (9%) with clinically suspected HIT

Oliveira et al, Arch Internal Med, vol. 168 (1);Jan. 14, 2008.

Heparin and Thrombocytopenia

• Many possible etiologies of thrombocytopenia in patientsacutely ill

Drug-induced, immune-mediated thrombocytopenia (ITP), sepsis, DIC, consumptive process

Heparin and Thrombocytopenia

Clinical Suspicion for HIT

• Time course of thrombocytopenia could be consistent with HIT

Starting with SQ UFH or IV UFH

New thrombotic event

• ? Too close to initiating SQ heparin

10

Clinical Suspicion for HIT

• Exposure to heparin after surgical procedure

• If sufficient clinical suspicion:Need to start direct thrombin inhibitor

Diagnostic Questions

• Was the DVT unrelated to HIT, but more due to risk of DVT after surgery and inpatient hospitalization?

Either way needs systemic anticoagulation

Treatment• Laboratory testing (functional assay)

positive for HIT

• Systemic anticoagulation with a direct thrombin inhibitor (argatroban)

Treatment• After sufficient recovery of platelet

count to near normal:Warfarin started concurrently with argatroban

Argatroban discontinued after INR therapeutic

• Warfarin therapy continued for 4-6 months

11

Case Presentation #3• 59 year old female admitted for unstable

angina. Underwent cardiac catherizationand subsequently a stenting procedure. Received heparin and abciximab(gp IIbIIIa agent) as a part of procedure, and subsequently placed on antiplatelet therapy

PMH: CAD

FH: CAD, DM

Platelets

0

50

100

150

200

250

300

350

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16

Days

IV Heparin

Platelet Transfusions

Platelet Transfusions

Thought Process• Abrupt and severe thrombocytopenia that

developed 6 days after therapy with both abciximab and heparin

• Acute drop in platelet countTime course of thrombocytopeniaSeverity of thrombocytopeniaWhich is the potentially offending agent?

Copyright ©2006 American Society of Hematology. Copyright restrictions may apply.

Warkentin, T. E. Hematology 2006;2006:408-414

Platelet count nadirs in heparin-induced thrombocytopenia (HIT), quinine-induced immune thrombocytopenic purpura (Q-ITP), and thrombotic

thrombocytopenic purpura (TTP) with absent ADAMTS-13 activity

12

Differential Diagnosis• Severe thrombocytopenia related to

the use of glycoprotein IIbIIIa agent versus HIT

• Timing of thrombocytopeniaThrombocytopenia abruptly occurred 7 days after abciximab and heparin

Differential DiagnosisTiming does not differentiate• Severity of thrombocytopenia more

consistent with abciximab induced thrombocytopenia

• Can occur within hours, or 5-8 days after therapy–Much sooner if recent

exposure/sensitization

Diagnosis• Overall clinical course and laboratory

findings more suggestive of abciximab induced thrombocytopenia

Direct thrombin inhibitor not started

• Gradual improvement in platelet count over the next 5-7 days

Supportive care with platelet transfusionsPF4 Antibody testing negative